ABSTRACT: Schizophrenia and other psychotic disorders are conditions of enormous costs to individuals, families and to the public. Treatment is often geared to large diagnostic groups, but psychotic conditions are comprised of a group of disorders that likely vary in their primary pathophysiology for which personalized treatments must be developed. Traditional DSM based disorders have not explained this heterogeneity. One possible driver of psychosis across disorders is hippocampal inflammation, which could be a target for person specific treatment. We have identified two separate inflammatory processes in schizophrenia using advanced imaging techniques. This study replicates the hippocampal inflammation finding in psychosis and tests if these are the source of psychotic symptoms. It furthermore tests the hypothesis that the inflammation is related to pathology in the gut-brain-axis (GBA) and particular species in the gut microbiome composition. The components of the GBA include resident microorganisms in the gut, parasympathetic (vagal) autonomic nervous systems (ANS) connections between the brain and the gut and circulating immune molecules. This study compares 50 cases, defined as having six months of chronic psychosis to 25 group mean age and sex matched comparison subjects without psychiatric disorders. To test the specificity of our results for psychosis we will also study 25 psychiatric cases without psychosis recruited from the same treatment settings. Imaging measures to determine hippocampal inflammation that is related to dysmyelination and inflammation for the microglia are 3 dimensional multivoxel MRSI imaging and diffusion kurtosis imaging (DKI) respectively. The arms interconnecting the gut to the brain through the vagal nerve and circulating inflammatory molecules will be examined individually and as an integrated system with respect to the two inflammation biomarkers. Gut inflammation will be assessed in stool samples by calprotectin levels, an inflammatory marker, and the genomic composition of the microbiome will be examined in highly sophisticated analyses. Using computational science and bioinformatics, this information will be integrated to test the relationship of the GBA to hippocampal inflammation. This multidisciplinary project brings scientists together from across the NYU medical center and includes expertise from Mt. Sinai, Columbia University and the University of Georgia's Medical Schools. Finding a microbiome or gut-brain-axis signature for hippocampal inflammation in psychotic persons will set the stage for the development of novel person specific treatments. If particular gut species are identified, future studies will examine their effects on the phenotype in mouse models for advancing novel treatments for psychosis.